The objective of this work is to develop an antibody-drug conjugate that will be useful against B-cell malignancies that express the CD74 antigen. More specifically, the conjugate will be a doxorubicin derivative attached to the complementarity-determining region-grafted (humanized) monoclonal antibody termed hLL1. The agent in this project will be developed for the multiple myeloma indication, but the same agent would be expected to be useful against any CD-74-expressing malignancy, including non-Hodgkin's lymphoma (NHL). This SBIR Phase I application will continue to explore the efficacy of the doxorubicin-hLL1 conjugate in a preclinical animal model of human multiple myeloma, since a preliminary indication of efficacy has now already been demonstrated. We expect to see significant efficacy at low doses of administered conjugate, and, hopefully, cures of animals at higher and/or multiple doses. With continuing positive efficacy data, the production of the conjugate will be scaled up to multi-grams of material. In vitro cell binding studies will be done to show that drug conjugation has not impinged antibody-antigen binding characteristics. Studies of the biodistributions of doxorubicin and hLL1 from the conjugate will be carried out, using mass spectrometry and radiolabeled antibody, respectively, to show that localization is antibody specific and cellular antibody uptake can be correlated with cellular anthracycline uptake. In this Phase I SBIR work, feasibility will be shown by a quantifiable demonstration of in vivo efficacy, and the therapeutic index of dox-hlL1 will be determined at both single and multiple weekly doses. With Promising data, SBIR Phase II will support the efforts to transfer the MAb-drug conjugate to a Phase I or Phase I/II clinical trial in multiple myeloma or, in another B-cell malignnacy such as NHL. Positive results in such a Phase I or Phase I/II clinical trial will lead to pivotal studies directed toward securing an FDA-approved antibody-drug conjugate for the selected disease indication.